Omeprazole is chemically termed as 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole. The S-enantiomer is chemically known as (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl}-1H-benzimidazole and hence named “esomeprazole.” The magnesium salt of esomeprazole is represented by formula I.

Esomeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease and Zollinger-Ellison syndrome. Esomeprazole is the S-enantiomer of omeprazole (marketed as Losec/Prilosec).
A process for asymmetric oxidation of sulphides to sulfoxides has been developed by Kagan and co-workers (J. Am. Chem. Soc. 1984; 106, 8188-8193), the oxidation is performed by using tert-butyl hydroperoxide (TBHP) as oxidizing agent in the presence of one equivalent of a chiral complex.
Various metal catalysed enantioselective oxidations or stoichiometric transition-metal-promoted reactions are described in the literature to prepare chiral sulfoxides by oxidation of the corresponding sulphides (Kagan H. B. In Catalytic Asymmetric Synthesis; Madesclaire M. Tetrahedron 1986; 42, 5459-5495; Procter D. J. Chem. Soc Perkin Trans 2000; 835-871; Khiar, N. J. Org. Chem. 2002, 67, 345). Metal catalysed enantioselective oxidations involve a metal catalyst complexed with a chiral ligand such as diethyl tartrate, trialkanolamine titanium (IV) complex, zirconium (IV) complexes etc. in the presence of various oxidants.
Omeprazole and therapeutically acceptable salts thereof, are first disclosed in EP 5129 and U.S. Pat. No. 4,255,431. The specific alkaline salts of omeprazole are also disclosed in U.S. Pat. Nos. 4,738,974, 5,714,504 and 5,877,192.
The resolution processes of racemates of omeprazole are for example disclosed in DE 4035455 and WO 94/27988.
An enantioselective synthesis of omeprazole by asymmetric oxidation is reported in WO 96/02535 (equivalent patents U.S. Pat. No. 5,948,789 and EP 0773940), which claims a process for enantioselective synthesis of the sulphoxide either as a single enantiomer or in an enantiometrically enriched form characterized in that a pro-chiral sulphide is oxidized in an organic solvent with an oxidizing agent in the presence of a chiral titanium complex optionally in the presence of a base, wherein the titanium complex has been prepared in the presence of the pro-chiral sulphide. From the description and the examples of the patent it is clearly understood that the absence of base yields a product having low enantiomeric purity as shown in examples 7 and 8. An excess enantioselectivity is obtained due to the presence of base in the reaction and preparation of the chiral complex in the presence of the pro-chiral sulphide. Examples 6, 7, 8, A, B and C in WO 96/02535 disclose processes for preparing the sulphoxide in the absence of a base. The amount of desired sulphoxide produced in the exemplified processes ranges from 22 to 31%.
Preparations of optically pure sulfoxides are claimed in WO 04/02982. The patent discloses a method of forming transition metal complexes at acid sulfoxide group which is reacted with a chiral acid to form an addition product, followed by separation.
U.S. Pat. No. 6,369,085 discloses various forms of esomeprazole magnesium trihydrate and dihydrate prepared from the corresponding potassium salt.
EP 0897386 claims a process for the preparation of the magnesium salt of esomeprazole comprising direct conversion of the sulphoxide to the magnesium salt in the presence of an organic base with a pKa from 7-12 and a magnesium source.
WO 04/046134 discloses crystalline Form II of esomeprazole magnesium trihydrate.
Amorphous esomeprazole magnesium and a process for its preparation are disclosed in patents WO 01/87831, WO 2004037253, US 2003-212274 and WO 06/96709.
WO 05/23797 discloses novel salts of R and S omeprazole.
US 2006-0089386 discloses a process in which sulfoxide derivatives are treated with a chiral acid such as camphor sulfonyl chloride followed by fractional crystallization, deprotection and conversion to a salt.
A similar method is also disclosed in WO 05/116011 and US 2006-166986 in which benzimidazole sulfide derivatives are reacted with a chiral acid reagent, oxidized, followed by separation of diastereomers, finally deprotection.
U.S. Pat. No. 6,369,085 discloses esomeprazole magnesium dihydrate Form A and B. The process for preparation of esomeprazole magnesium dihydrate Form A is not industrially efficient as it often results in the dihydrate being converted to the trihydrate or amorphous esomeprazole magnesium. This process is disadvantageous as the polymorph A of the dihydrate cannot be obtained consistently as the wet dihydrate gets converted during drying to the trihydrate or amorphous form. Use of acetone to slurry the product and dry, results in an inconsistent polymorph.
Hence there is a need for a robust process for the synthesis of esomeprazole magnesium dihydrate in good yield consistently on a large scale and in a reproducible manner. The present invention provides an industrially suitable process for preparation of esomeprazole magnesium dihydrate. More particularly Form A of esomeprazole magnesium dihydrate.